Trimeric structure of TNF alpha, produced by Mus musculus, based on PDB structure 2TNF (1.4 Å Resolution). Different colors represent different monomers. Baeyens, KJ et al. (1999). Figure rendered using FirstGlance Jmol.
The tumor necrosis factor (TNF) superfamily refers to a group of cytokines that can cause cell death (apoptosis).
The first two members of the family to be identified were:
Tumor necrosis factor (TNF), formerly known as TNFα or TNF alpha, is the best-known member of this class. TNF is a monocyte-derived cytotoxin that has been implicated in tumor regression, septic shock, and cachexia. The protein is synthesized as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers. Both the mature protein and a partially processed form of the hormone can be secreted after cleavage of the propeptide.
Nineteen proteins have been identified as part of the TNF family on the basis of sequence, functional, and structural similarities. They include:
Tumor necrosis factor (TNF) (also known as cachectin  or TNF alpha) is a cytokine that has a wide variety of functions. It can cause cytolysis of certain tumor cell lines; it is involved in the induction of cachexia; it is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion; it can stimulate cell proliferation and induce cell differentiation under certain conditions.
T cell antigen gp39 (CD40L), a cytokine that seems to be important in B-cell development and activation.
CD27L, a cytokine that plays a role in T-cell activation. It induces the proliferation of co-stimulated T cells and enhances the generation of cytolytic T cells.
CD30L, a cytokine that induces proliferation of T cells.
FASL, a cell surface protein involved in cell death.
4-1BBL, an inducible T cell surface molecule that contributes to T-cell stimulation.
OX40L, a cell surface protein that co-stimulates T cell proliferation and cytokine production.
TNF-related apoptosis inducing ligand (TRAIL), a cytokine that induces apoptosis.
Model of hydrogen bond between Asn34 of subunit A and Arg82 of subunit C, produced by M. musculus, based on PDB structure 2TNF. The residues participating the hydrogen bond are shown in stick. The short bond length, 2.84Å, highly suggests a strong hydrogen bond that supports the tertiary structure. Baeyens, KJ et al. (1999). Generated in Chimera.
All these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognized by their specific receptors. Strong hydrogen bonds between the monomers stabilize the tertiary structure. One such example is the Asn34-Arg82 hydrogen bond in the M. musculus TNF alpha. The PROSITE pattern for this family is located in a beta-strand in the central section of the protein that is conserved across all members.
All members of the TNF family, with the exception of the secreted lymphotoxin and a proliferation-inducing ligand (APRIL), are type II transmembrane proteins that protrude from immune cells. Such membrane-bound TNF ligands frequently signal back to the immune cells when they contact and bind their cognate receptors on other cells.
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